The present invention relates to a novel type of preparations suitable for the application of different agents in the form of a minuscule droplet or, in particular, a vesicle consisting of one or a few membrane-like amphiphile assemblies. These can mediate the transport of agents into and through a series of natural permeability barriers or through the constrictions in such barriers; for example, through intact skin or similar organs. The invention further relates to a procedure for the large-scale production of such carriers. As a special example, non-invasive application of antidiabetics is described for the case of insulin.
The application of various agents is often hampered by the presence of barriers with a low permeability to such agents. Owing to skin impermeability, for example, many common therapeutic agents must be applied per os or parenterally (i.v., i.m., i.p.). Intrapulmonary and intranasal applications of aerosols, the use of rectal formulations, gels for mucous applications, or use of occular formulations are only practicable in certain areas and not for all types of drugs. The transport of different agents into plant tissues is subject to even more severe constraints due to the high permeability barrier of the cuticular wax layers.
Noninvasive drug application through permeability barriers thus would be advantageous in many cases. In humans and animals one would expect such a percutaneous application of agents to protect the agents from degradation in the gastro-intestinal tract; modified drug distribution could possibly also be achieved. Such drug application, moreover, would influence the pharmacokinetics of the agent molecules and permit simple as well as multiple noninvasive therapy. (Karzel K., Liedtke, R. K. (1989) Arzneim. Forsch./Drug Res. 39, 1487-1491). In the case of plants, improved penetration into or through the cuticle could reduce the drug concentration required for a given application and thus significantly diminish pollution problems (Price, C. E. (1981) In: The plant cuticle (D. F. Cutler, K. L. Alvin, C. E. Price, Edits.), Academic, New York, pp. 237-252).
There are many reports on different attempts to increase the permeability of intact skin by suitable manipulations (cf. Karzel und Liedtke, op. cit.). Jet injection (Siddiqui & Chien (1987) Crit. Rev. Ther. Drug. Carrier. Syst. 3, 195-208.), the use of electric fields (Burnette & Ongpipattanakul (1987) J. Pharm. Sci. 76, 765-773) or chemical penetration enhancers, such as solvents and surfactants, are particularly worth mentioning. A long list of additives which have been used to enhance the penetration of one particular water soluble agent (Nolaxon) into skin, for example, is given in the work by Aungst et al. (1986, Int. J. Pharm. 33, 225-234). This list encompasses nonionic substances (including long-chain alcohols, surfactants, zwitterionic phospholipids, etc.), anionics (most notably fatty acids), cationic long-chain amines, sulfoxides as well as different amino-derivatives; amphotheric glycinates and betaines are also mentioned. Despite all this, the problem of agent penetration into skin has as yet not at all--or not satisfactorily--been solved.
A survey of procedures used for increasing the penetration of agents through a plant cuticle is given in the work by Price (1981, op.cit.). To date it has been common to simply add chemical penetration enhancers to the mixture of agent and other molecules; applications to human skin were the only case in which additives were sometimes applied in advance, in the form of an organic solution. The reason for this application form was the current concept for the action of penetration enhancers: to date one has studied, discussed, and believed that, in general, any facilitated agent penetration is a consequence of skin fluidization, on the one hand (Golden et al., (1987) J. Pharm. Sci. 76, 25-28). (This phenomenon is normally associated with a destruction of the skin surface and of its protective shield and thus is undesired.) On the other hand, it has been shown that some agents can permeate through skin in the form of low-molecular weight complexes with added molecules (Green et al., (1988) Int. J. Pharm. 48, 103-111).
Methods deviating from the ones already described have brought little improvement to date. The use of lipoidal carriers, the liposomes, on intact skin, which has been theoretically discussed by several authors, was mainly aimed at modifying the agent's pharmacokinetics (Patel, Bioch. Soc. Trans., 609th Meeting, 13, 513-517, 1985, Mezei, M. Top. Pharm. Sci. (Proc. 45th Int. Congr. Pharm. Sci.F.I.P.) 345-58 Elsevier, Amsterdam, 1985). Thus far, all proposal of this kind, moreover, involved the use of standard lipid vesicles (liposomes) which cannot penetrate the skin at all or permeate through the skin very inefficiently, as is shown in this patent application. Patent applications nos. JP 61/271204 A2 [86/271204] refer to a related use of liposomes in which hydrochinonglucosidal is employed to improve the stability of the agent.
Hitherto available preparations for percutaneous use have mostly been applied under occlusion; in the case of liposomal preparations, this was even a general rule. The corresponding preparations only contained small or lipophilic substances, as well as a limited number of skin-fluidizing additives. Correspondingly, they afforded only partial control over the pharmacokinetic properties of final preparations. In an attempt to improve this situation a proposal was made (WO 87/1938 A1) to use drug-carrying lipid vesicles in combination with a gelatinizing agent as a transdermal patch. This has prolonged drug action but has not increased the skin-penetration capability of the drug itself. Through massive use of penetration enhancers (polyethylene glycol and fatty acids) and of lipid vesicles, Gesztes und Mezei (1988, Anesth. Analg. 67, 1079-1081) have succeeded in inducing local analgesia with lidocaine-containing carriers; however, the overall effectiveness of the drug in this preparation was relatively low and its effects were only observed several hours after the beginning of an occlusive application.
By a specially designed formulation we have succeeded in obtaining results which were dramatically better than those of Gesztes and Mezei. Our carrier formulations consisted of filtered lipid vesicles (liposomes) which also contained some detergents, with a declared optimum lipid/surfactant content of 1-40/1, in practice mainly around 4/1.
These results provided a basis for German patent application P 40 26 834.9-41 which also refers to German patent application P 40 26 833.0-43; the latter deals with the problem of liposome fabrication.
Since then, we have unexpectedly discovered that certain criteria, described in this application, may be formulated for the qualification of drug carriers as suitable for the penetration into and through a permeability barrier. The main requirement of such a drug carrier--which in the following is called a transfersome--is that it is sufficiently elastic to penetrate through the constrictions in a barrier, such as skin. In the case of transfersomes consisting of phosphatidylcholine and sodium cholate this condition is fulfilled when the edge tension of a carrier is below 10 Piconewton; similar values are also likely to pertain to other, related systems. Carriers which are capable of creating a gradient after an application are particularly useful; this is due to the fact that they have a spontaneous tendency for penetration through permeability barriers.